TY - JOUR
T1 - HB-EGF–EGFR signaling in bone marrow endothelial cells mediates angiogenesis associated with multiple myeloma
AU - Rao, Luigia
AU - Giannico, Donato
AU - Leone, Patrizia
AU - Solimando, Antonio Giovanni
AU - Maiorano, Eugenio
AU - Caporusso, Concetta
AU - Duda, Loren
AU - Tamma, Roberto
AU - Mallamaci, Rosanna
AU - Susca, Nicola
AU - Buonavoglia, Alessio
AU - Da Vià, Matteo Claudio
AU - Ribatti, Domenico
AU - De Re, Vallì
AU - Vacca, Angelo
AU - Racanelli, Vito
N1 - Funding Information:
Funding: This work was supported by Associazione Italiana per la Ricerca sul Cancro (AIRC, Milan, Italy) through the Special Program Molecular Clinical Oncology 5 per 1000 (no. 9965 to A.V.) and Investigator Grant (no. 20441 to VR) and by Fondo di Sviluppo e Coesione 2007–2013—APQ Ricerca Regione Puglia “Programma regionale a sostegno della specializzazione intelligente e della sostenibilità sociale ed ambientale—FutureInResearch”. L.R. was supported by studentship from Federazione Italiana per la Ricerca sul Cancro (FIRC), Milan, Italy (project code 16678). The sponsors of this study are non-profit organizations that support science in general; they had no role in gathering, analyzing or interpreting the data.
Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/1
Y1 - 2020/1
N2 - Epidermal growth factor receptor (EGFR) and its ligand heparin-binding EGF-like growth factor (HB-EGF) sustain endothelial cell proliferation and angiogenesis in solid tumors, but little is known about the role of HB-EGF–EGFR signaling in bone marrow angiogenesis and multiple myeloma (MM) progression. We found that bone marrow endothelial cells from patients with MM express high levels of EGFR and HB-EGF, compared with cells from patients with monoclonal gammopathy of undetermined significance, and that overexpressed HB-EGF stimulates EGFR expression in an autocrine loop. We also found that levels of EGFR and HB-EGF parallel MM plasma cell number, and that HB-EGF is a potent inducer of angiogenesis in vitro and in vivo. Moreover, blockade of HB-EGF–EGFR signaling, by an anti-HB-EGF neutralizing antibody or the EGFR inhibitor erlotinib, limited the angiogenic potential of bone marrow endothelial cells and hampered tumor growth in an MM xenograft mouse model. These results identify HB-EGF–EGFR signaling as a potential target of anti-angiogenic therapy, and encourage the clinical investigation of EGFR inhibitors in combination with conventional cytotoxic drugs as a new therapeutic strategy for MM.
AB - Epidermal growth factor receptor (EGFR) and its ligand heparin-binding EGF-like growth factor (HB-EGF) sustain endothelial cell proliferation and angiogenesis in solid tumors, but little is known about the role of HB-EGF–EGFR signaling in bone marrow angiogenesis and multiple myeloma (MM) progression. We found that bone marrow endothelial cells from patients with MM express high levels of EGFR and HB-EGF, compared with cells from patients with monoclonal gammopathy of undetermined significance, and that overexpressed HB-EGF stimulates EGFR expression in an autocrine loop. We also found that levels of EGFR and HB-EGF parallel MM plasma cell number, and that HB-EGF is a potent inducer of angiogenesis in vitro and in vivo. Moreover, blockade of HB-EGF–EGFR signaling, by an anti-HB-EGF neutralizing antibody or the EGFR inhibitor erlotinib, limited the angiogenic potential of bone marrow endothelial cells and hampered tumor growth in an MM xenograft mouse model. These results identify HB-EGF–EGFR signaling as a potential target of anti-angiogenic therapy, and encourage the clinical investigation of EGFR inhibitors in combination with conventional cytotoxic drugs as a new therapeutic strategy for MM.
KW - Bone marrow angiogenesis
KW - EGFR
KW - Endothelial cells
KW - HB-EGF
KW - Multiple myeloma
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U2 - 10.3390/cancers12010173
DO - 10.3390/cancers12010173
M3 - Article
VL - 12
JO - Cancers
JF - Cancers
SN - 2072-6694
IS - 1
M1 - 173
ER -